Although the fluid-mosaic model of plasma membrane architecture postulates that proteins in the plasma membrane freely diffuse among a field of wheat lipid bilayer, it has become clear that the plasma membrane is not a homogenous structure and distinct protein/lipid structures, or microdomains, exist that allow for the local concentration (or exclusion) of particular proteins. Peptide-loaded MHC-II (pMHC-II) complexes are displayed on the plasma membrane of APCs to allow for efficient recognition by CD4 T cells and T cells are known to recognize and be stimulated by very small amounts of pMHC-II. We were the first to report that pMHC-II is constitutively associated with plasma membrane microdomains, termed lipid rafts, and that raft association increases the local density of pMHC-II to support T cell activation by small numbers of pMHC-II complexes. We have been attempting to determine the kinetics by which newly synthesized pMHC-II complexes associate with these structures and to visualize the appearance of lipid raft pMHC-II clusters on the surface of APCs. Our current work is to identify the molecular signals that regulate pMHC-II association with lipid membrane domains and to specifically determine whether ubiquitination plays a role MHC-II localization to lipid raft microdomains.